Chae Moon Hong

Prognostic implication of intratumoral metabolic heterogeneity in invasive ductal carcinoma of the breast.

BackgroundThe purpose of this study was to evaluate the prognostic implication of findings of intratumoral metabolic heterogeneity on pretreatment 18F-FDG PET/CT scans in patients with invasive ductal carcinoma (IDC) of the breast.MethodsOne hundred and twenty-three female IDC patients who underwent pretreatment 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) scans were retrospectively evaluated in this study. The heterogeneity factor (HF) defined as the derivative (dV/dT) of a volume threshold function from 40% to 80%, was computed for each primary tumor. Other metabolic PET parameters (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) were measured. The HF was compared with clinicopathologic factors and other PET parameters. Univariate and multivariate analyses for the overall survival (OS) were performed.ResultsThe HF ranged from 0.02 to 6.72 (mean, 0.35 ± 0.82) and significantly correlated with MTV (r = 0.955; p < 0.0001) and TLG (r = 0.354; p = 0.0001). The HF was significantly higher (implying more heterogeneity) in tumors with higher T and N stages. The optimal cut-off values for the OS determined using a receiver operating characteristic (ROC) curve were 0.34 for the HF, 5.6 for SUVmax, 8.55 cm3 for MTV, and 14.43 for TLG. The OS rate among the 123 patients was 86.2%. T stage (1, 2 vs. 3, 4), N stage (0, 1 vs. 2, 3), M stage (0 vs. 1), ER status (+ vs. –), SUVmax (≤ 5.6 vs. > 5.6), MTV (≤ 8.55 cm3 vs. > 8.55 cm3), TLG (≤ 14.43 vs. > 14.43), and HF (< 0.34 vs. ≥ 0.34) affected the OS on univariate analysis. After adjustment for the effects of TNM stage and ER status, the HF and MTV were significant predictors of OS. Among the PET parameters, the best prognostic factor for OS was the HF.ConclusionsIntratumoral metabolic heterogeneity correlated closely with the MTV and significantly affected the OS in IDC patients. The HF may act as a robust surrogate marker for the prediction of OS in IDC patients.

Prognostic Value of Primary Tumor Uptake on F-18 FDG PET/CT in Patients with Invasive Ductal Breast Cancer

PurposeTo determine the prognostic implications of pretreatment F-18 FDG PET/CT in patients with invasive ductal breast cancer (IDC), we evaluated the relationship between FDG uptake of the primary tumor and known prognostic parameters of breast cancer. Prognostic significance of tumoral FDG uptake for the prediction of progression-free survival (PFS) was also assessed.Materials and MethodsFifty-five female patients with IDC who underwent pretreatment F-18 FDG PET/CT were enrolled. The maximum standardized uptake value of the primary tumor (pSUVmax) was compared with clinicopathological parameters including tumor size, grade, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor2 (HER2), axillary lymph node (LN) metastasis, and stage. The prognostic value of pSUVmax for PFS was assessed using the Kaplan-Meier method.ResultsA high pSUVmax was significantly related to a higher stage of tumor size (P < 0.05), grade (P < 0.001), and stage (P < 0.001). pSUVmax was significantly higher in ER-negative tumors (P < 0.001), PR-negative tumors (P < 0.001), and positive LN metastasis (P < 0.01), but not different according to HER2 status. pSUVmax was significantly higher in patients with progression compared to patients who were disease-free (10.6 ± 5.1 vs. 4.7 ± 3.5, P < 0.001). A receiver-operating characteristic curve demonstrated a pSUVmax of 6.6 to be the optimal cutoff for predicting PFS (sensitivity; 86.7%, specificity; 82.5%). The patients with a high pSUVmax (more than 6.6) had significantly shorter PFS compared to patients with a low pSUVmax (P < 0.0001).ConclusionspSUVmax on pretreatment F-18 FDG PET/CT could be used as a good surrogate marker for the prediction of progression in patients with IDC.

Current Perspectives on In Vivo Noninvasive Tracking of Extracellular Vesicles with Molecular Imaging

Clinical and preclinical in vivo tracking of extracellular vesicles (EVs) are a crucial tool for the development and optimization of EV-based diagnosis and treatment. EVs have gained interest due to their unique properties that make them excellent candidates for biological applications. Noninvasive in vivo EV tracking has allowed marked progress towards elucidating the mechanisms and functions of EVs in real time in preclinical and clinical studies. In this review, we summarize several molecular imaging methods that deal with EVs derived from different cells, which have allowed investigations of EV biodistribution, as well as their tracking, delivery, and tumor targeting, to determine their physiological functions and to exploit imaging-derived information for EV-based theranostics.

Prognostic Significance of Intratumoral Metabolic Heterogeneity on 18F-FDG PET/CT in Pathological N0 Non-Small Cell Lung Cancer.

Purpose The aim of the study was to evaluate the prognostic significance of intratumoral metabolic heterogeneity on pretreatment 18F-FDG PET/CT in patients with lung cancer who were pathologically N0 (pN0) after curative surgical resection. Methods We examined 119 patients (M/F = 79/40; mean age, 64.6 ± 9.0 years) who had undergone pretreatment 18F-FDG PET/CT and were diagnosed as pN0 after curative surgery for adenocarcinoma (ADC; n = 67) or squamous cell carcinoma (SQCC; n = 52). Heterogeneity factor (HF) and other metabolic parameters (SUVmax, metabolic tumor volume [MTV] and total lesion glycolysis [TLG]) for the primary lesions were measured, and the results were analyzed for recurrence. The HF, defined as the derivative of the volume-threshold function from 20% to 80%, was computed for primary lesions. Univariate and multivariate analyses for recurrence were performed using the Kaplan-Meier method and using the Cox proportional hazards model. Results SUVmax, MTV, TLG, and HF were statistically different between patients with ADC and SQCC. Forty-one (34.5%) of 119 patients experienced recurrence (ADC, 25/67 = 37.3% vs. SQCC, 16/52 = 30.8%). Results of univariate analysis indicate that SUVmax, MTV, TLG, and HF in ADC and TLG and HF in SQCC were predictors for recurrence. After adjusting for sex, age, and histological grade in multivariate analysis, high SUVmax, MTV, TLG, and HF in ADC exhibited an association with increased risk of recurrence. Conclusions Metabolic parameters and heterogeneity of primary tumor on pretreatment 18F-FDG PET/CT can predict recurrence in pN0 NSCLC patients of ADC type who have undergone curative surgery but not in patients of SQCC type.

Extracellular vesicles from mesenchymal stem cells activates VEGF receptors and accelerates recovery of hindlimb ischemia

&NA; Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are potential therapies for various diseases, but their angiogenic mechanisms of therapeutic efficacy remain unclear. Here, we describe how MSC‐EVs, activates VEGF receptors and downstream angiogenesis pathways. Mouse MSC‐EVs were isolated from cell culture medium and characterized using transmission electron microscopy, nanoparticle analysis, and western blotting. In vitro migration, proliferation, and tube formation assays using endothelial cells were used to assess the angiogenic potential of MSC‐EVs, and revealed higher levels of cellular migration, proliferation, and tube formation after treatment. qRT‐PCR and western blotting (WB) revealed higher protein and mRNA expression of the angiogenic genes VEGFR1 and VEGFR2 in mouse SVEC‐4 endothelial cells after MSC‐EVs treatment. Additionally, other vital pro‐angiogenic pathways (SRC, AKT, and ERK) were activated by in vitro MSC‐EV treatment. WB and qRT‐PCR revealed enriched presence of VEGF protein and miR‐210‐3p in MSC‐EV. The hindlimb ischemia mouse model was established and MSC‐EVs with or without Matrigel (EV‐MSC + Gel) were injected into the ischemic area and blood reperfusion was monitored using molecular imaging techniques. The in vivo administration of MSC‐EVs increased both blood reperfusion and the formation of new blood vessels in the ischemic limb, with the addition of matrigel enhancing this effect further by releasing EVs slowly. MSC‐EVs enhance angiogenesis in ischemic limbs, most likely via the overexpression of VEGFR1 and VEGFR2 in endothelial cells. These findings reveal a novel mechanism of activating receptors by MSC‐EVs influence the angiogenesis. Graphical abstract Figure. No caption available.

Neurolymphomatosis on F-18 FDG PET/CT and MRI Findings: A Case Report.

Neurolymphomatosis is a rare manifestation of malignant lymphoma. A 74-year-old man, in complete remission from diffuse large B cell lymphoma, presented with a loss of pain and temperature sensation in the left hemiface and left upper extremity, and motor weakness in the left upper and both lower extremities. Cerebrospinal fluid analysis and brain magnetic resonance imaging (MRI) findings were negative. Combined fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) revealed multiple linear hypermetabolic lesions along the mandibular branch of the left trigeminal nerve, left brachial plexus, right axillary nerve, right suprarenal plexus, right adrenal gland, right femoral nerve, and both sciatic nerves, which corresponded to the patient’s complex neurologic symptoms. C-spine and pelvic MRI revealed diffuse thickening with enhancement in the left brachial plexus and in the proximal portion of the left sciatic nerve, but negative findings for other sites identified by FDG-PET/CT. These findings suggest that FDG-PET/CT can detect peripheral nerve infiltration by malignant lymphoma earlier than MRI. Thus, if a patient with a history of lymphoma presents with neurologic symptoms, FDG-PET/CT should be performed to evaluate neurolymphomatosis.

Extra-thoracic tumor burden but not thoracic tumor burden on 18F-FDG PET/CT is an independent prognostic biomarker for extensive-disease small cell lung cancer

PURPOSE The aim of this study was to evaluate the relationship and difference in prognostic significance between whole-body tumor burden, thoracic tumor burden, and extra-thoracic tumor burden on (18)F-FDG PET/CT for patients with extensive-disease small cell lung cancer (ED-SCLC). MATERIALS AND METHODS We performed a retrospective, two-center analysis for patients with ED-SCLC who underwent pretreatment (18)F-FDG PET/CT. Metabolic tumor burden was estimated using whole-body metabolic tumor volume (MTV(WB)), thoracic metabolic tumor volume (MTV(TRX)), extra-thoracic metabolic tumor volume (MTV(EXT)), and the number of extra-thoracic tumor foci. Uni- and multivariate analyses were performed using various clinical factors and the metabolic indices. RESULTS A total of 91 patients were eligible for this study. MTV(WB) showed stronger correlation with MTV(EXT) than MTV(TRX) (r(2) = 0.804 vs. 0.132, p < 0.001, both), whereas no correlation was observed between MTV(EXT) and MTV(TRX) (r(2) = 0.007, p = 0.428). Patients with smaller MTV(WB), MTV(EXT), and extra-thoracic tumor foci showed longer survival than patients with larger MTV(WB), MTV(EXT), and extra-thoracic tumor foci, respectively, whereas the survival difference between patients with smaller MTV(TRX) and those with larger MTV(TRX) was not significant. Results of uni- and multivariate analyses showed that ECOG performance status (HR = 2.31, p = 0.015), initial chemotherapy cycles (HR = 0.24, p < 0.001), and the number of extra-thoracic tumor foci (HR = 2.75, p < 0.001) were independent prognostic factors for overall survival, and initial chemotherapy cycles (HR = 0.25, p < 0.001), and MTV(EXT) (HR = 2.04, p = 0.013) were independent prognostic factors for progression-free survival. CONCLUSION These data provide evidence indicating that extra-thoracic tumor burden but not thoracic tumor burden is an independent prognostic biomarker for ED-SCLC, and support further exploration of novel treatment strategies targeting extra-thoracic tumor burden in order to improve the clinical outcomes of patients with ED-SCLC.

Superiority of delayed risk stratification in differentiated thyroid cancer after total thyroidectomy and radioactive iodine ablation.

AimThe aim of this study was to validate the effectiveness of delayed risk stratification (DRS) in predicting structural progression and compare the predictive value of American Thyroid Association (ATA) risk stratification with that of DRS in patients with differentiated thyroid cancer (DTC). MethodsA total of 398 patients with DTC who underwent surgery followed by radioactive iodine ablation were enrolled. Patients were categorized as having excellent response, acceptable response, biochemical incomplete response, or structural incomplete response at 8–15 months’ evaluation after radioactive iodine ablation for DRS. Effectiveness of DRS was evaluated according to structural progression-free survival (PFS; median follow-up, 10.7 years). ResultsA total of 229 patients (57.5%) were classified as having excellent response, 78 (19.6%) as having acceptable response, 62 (15.6%) as having biochemical incomplete response, and 29 patients (7.3%) as having structural incomplete response. After DRS, 60.2% of intermediate-risk patients and 20.5% of high-risk patients were shifted to the excellent response category. Sixty-nine patients (17.3%) showed structural progression. DRS showed statistical difference in PFS (hazard ratio, 4.268; 95% confidence interval, 3.258–5.477; P<0.001). In multivariate analysis of ATA risk stratification and DRS, DRS was significantly associated with PFS (hazard ratio, 4.383; 95% confidence interval, 3.250–5.912; P<0.001), but ATA risk stratification was not. There was no significant difference in deviances between the use of DRS alone and the use of both DRS and ATA risk stratification (&khgr;2=0.103, d.f.=1, P=0.748). ConclusionDRS is superior to ATA risk stratification in predicting structural disease progression for DTC patients.

An Update on in Vivo Imaging of Extracellular Vesicles as Drug Delivery Vehicles

Extracellular vesicles (EVs) are currently being considered as promising drug delivery vehicles. EVs are naturally occurring vesicles that exhibit many characteristics favorable to serve as drug delivery vehicles. In addition, EVs have inherent properties for treatment of cancers and other diseases. For research and clinical translation of use of EVs as drug delivery vehicles, in vivo tracking of EVs is essential. The latest molecular imaging techniques enable the tracking of EVs in living animals. However, each molecular imaging technique has its certain advantages and limitations for the in vivo imaging of EVs; therefore, understanding the molecular imaging techniques is essential to select the most appropriate imaging technology to achieve the desired imaging goal. In this review, we summarize the characteristics of EVs as drug delivery vehicles and the molecular imaging techniques used in visualizing and monitoring EVs in in vivo environments. Furthermore, we provide a perceptual vision of EVs as drug delivery vehicles and in vivo monitoring of EVs using molecular imaging technologies.

Redifferentiation of Radioiodine Refractory Differentiated Thyroid Cancer for Reapplication of I-131 Therapy

Although most differentiated thyroid cancers show excellent prognosis, treating radioiodine refractory differentiated thyroid cancer (RR-DTC) is challenging. Various therapies, including chemotherapy, radiotherapy, and targeted therapy, have been applied for RR-DTC but show limited effectiveness. Redifferentiation followed by radioiodine therapy is a promising alternative therapy for RR-DTC. Retinoic acids, histone deacetylase inhibitors, and peroxisome proliferator-activated receptor-gamma agonists are classically used as redifferentiation agents, and recent targeted molecules are also used for this purpose. Appropriate selection of redifferentiation agents for each patient, using current knowledge about genetic and biological characteristics of thyroid cancer, might increase the efficacy of redifferentiation treatment. In this review, we will discuss the mechanisms of these redifferentiation agents, results of recent clinical trials, and promising preclinical results.